1. Field of the Invention
This invention pertains to the field of pharmaceutical chemistry and provides a stereoselective process for preparing .beta.-anomer enriched 2-deoxy-2,2-difluo-D-ribofuranosyl-3,5-hydroxy blocked-1-alkyl and aryl sulfonate intermediates used in the preparation of known anit-cancer and anti-viral nucleoside agents.
2. State of the Art
Processes for preparing anti-cancer and anti-viral .beta.-nucleoside agents involve the stereochemical inversion of furanose (carbohydrate) intermediates bearing a leaving group at the anomeric center. Therefore, when a .beta.-anomer nucleoside is the desired product, an .alpha.-anomer enriched carbohydrate intermediate is preferably used in S.sub.N 2 coupling reactions.
The most frequently used coupling intermediate is 1-chloro-2-deoxy-3,5-(di-O-p-toluoyl)-.alpha.-D-erythropentofuranose, which was first prepared by Hofer, Chem. Ber., 93, 2777 (1960). This compound is crystalline and exists exclusively as an .alpha.-anomer. However, coupling reactions using Hofer's .alpha.-chloro anomer carbohydrate to prepare 2-deoxyribofuranosyl nucleosides were nonstereoselective. Hubbard, et. al., Nucleic Acids, 12, 6827 (1984) later studied Hofer's results and found that the .alpha.-chloro carbohydrate intermediate anomerized in the organic solvent used at ambient temperatures to form the corresponding .beta.-chloro anomer carbohydrate intermediate. Therefore, anomerization was responsible for the non-stereoselective nature of Hofer's coupling reaction. Hubbard, et. al., evaluated the anomerization of the .alpha.-chloro carbohydrate in several solvents to find solvents that would hold the effects of anomerization to a minimum so that a high yield of the desired .beta.-nucleoside product could be obtained.
Besides chloro, alkyl and aryl sulfonyloxys represent other types of leaving groups that have been evaluated. However, due to the instability of some 2-deoxy-D-erythropentofuranosyl sulfonate intermediates, carbohydrates that contain sulfonyloxy leaving groups are conspicuously absent from the chemical literature and are rarely used in coupling.
U.S. Pat. Nos. 4,526,988 and 4,965,374 teach coupling reactions that employ anomeric mixtures of 2-deoxy-2,2-difluoro-D-ribofuranosyl-1-alkyl and aryl sulfonate intermediates to make 2'-deoxy-2',2'-difluoronucleosides. As a consequence of using anomeric mixtures, these processes are non-stereoselective for .beta.-anomer nucleosides and provide a 1:1 and 4:1 .alpha. to .beta. anomer ratio respectively, of 2'-deoxy-2',2'-difluoronucleosides.
In order to improve the stereoselectivity of the coupling reactions used to make 2'-deoxy-2',2'-difluronucleosides, Chou, et. al., in Pending U.S. patent application Ser. No. 07/902,135, found that carbohydrate intermediates containing iodo, bromo and sulfonate leaving groups would stereoselectively couple under anionic coupling conditions and provide a .beta. to .alpha. anomer nucleoside ratio as high as 10:1. The method for making the sulfonate intermediates used by Chou is taught by Chou, et. al., in Pending U.S. patent application Ser. No. 07/902,305. The method involves obtaining an .alpha.-anomer enriched 2-deoxy-2,2-difluoro-ribofuranosyl-3,5-hydroxy protected-1-alkyl and aryl sulfonate intermediates from their corresponding .beta.-anomer enriched sulfonate intermediates by anomerizing .beta.-anomer enriched sulfonate intermediate with the conjugate anion of a sulfonic acid of the sulfonate.
Chou, et. al., in Pending U.S. patent application Ser. No. 07/902,143, teach a method for obtaining .beta.-anomer enriched 2-deoxy-2,2-difluoro-ribofuranosyl-3,5-hydroxy protected-1-aryl sulfonate intermediates from lactols. However, as .alpha.-anomers, these intermediates contain the wrong stereochemistry for providing .beta.-anomer nucleoside by S.sub.N 2 coupling. Therefore, in order to use them in S.sub.N 2 coupling, .beta.-anomer enriched carbohydrates must be converted to .alpha.-anomer enriched carbohydrates by equilibration.
Despite the foregoing advances, there continues to be a need for alternative stereoselective processes for preparing .beta.-anomer enriched 2-deoxy-2,2-difluororibofuranosyl-3,5-hydroxy protected-1-alkyl and aryl sulfonate intermediates.
It is an object of the present invention to provide a stereoselective process for preparing .beta.-anomer enriched 2-deoxy-2,2-difluoro-ribofuranosyl-3,5-hydroxy protected-1-alkyl and aryl sulfonate intermediates from highly reactive .alpha.-anomer enriched 2-deoxy-2,2-difluoro-ribofuranosyl-3,5-hydroxy protected-1-fluoroalkyl and fluoroaryl sulfonate intermediates.
Other objects and advantages of the present invention will become apparent from the following description of embodiments.